tbuckley/cabot-search huggingface dataset:
Phase I study of BTK inhibitor ibrutinib with temozolomide and radiation in newly-diagnosed glioblastoma (EQUILIBRIUM): Final trial report.
Authors: Manmeet Singh Ahluwalia, Ahmad Ozair, Atulya Aman Khosla, Neha Patel, Paul Elson, Erin Sennett Murphy, Jennifer S. Yu, Samuel T. Chao, John H. Suh, Glen Stevens, David M. Peereboom
Journal: Journal of Clinical Oncology (2023)

2067 Background: Novel therapeutic strategies are urgently needed in newly-diagnosed glioblastoma (GBM). Ibrutinib, an oral small molecule inhibitor of BTK, is currently being investigated for several B-cell malignancies and solid tumors. Preclinical evidence suggests ibrutinib in inhibiting cancer stem cell in glioblastoma. We sought to investigate the safety and tolerability of ibrutinib in nGBM. Methods: A non-randomized, prospective phase I trial was conducted in nGBM patients with Karnofsky performance status ≥70% and normal organ function, who received standard of care chemoradiation plus ibrutinib in a 3+3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60 Gy over 6 weeks with/without 75 mg/m 2 of temozolomide (TMZ). Secondary objective was to determine safety, overall survival (OS), and progression-free survival. Results: 26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib plus RT (ibru+RT) cohort. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ. All MGMT methylated and 2 unmethylated patients received ibrutinib+RT+TMZ. Remaining 9 unmethylated received ibru+RT. In ibru+RT+TMZ, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). EGFR amplification status was available for 22 patients, of which 8 (36%) were amplified. Survival outcomes are described, stratified using log-rank test. Conclusions: 420 mg of Ibrutinib daily is safe and feasible in combination with TMZ and radiation in nGBM. Outcomes of ibrutinib appears promising compared to historical survival data in the MGMT methylated cohorts. Further trials are planned. Clinical trial information: NCT03535350 . [Table: see text]
Nationwide utilization of palliative care in patients admitted for GI malignancies.
Authors: Rafaella Litvin, Ekrem Turk, Vaishali Deenadayalan, Michelle Ishaya, Mona Dasgupta, Ayobami Gbenga Olafimihan, Jay Vakil, Muhammad Bilal Ibrahim, Mihir Shah, Khaldun Obeidat, Navika Chhabra, Hafeez Shaka, Michael Russell Mullane
Journal: Journal of Clinical Oncology (2023)

e24114 Background: Gastrointestinal (GI) cancers account for a large proportion of cancer-related deaths and are often associated with significant impairment in quality of life, even at earlier stages. Although guidelines recommend early palliative care (PC) involvement in all patients with advanced cancer, and select patients at earlier stages, implementation of these practices has been highly variable. Methods: Using the National Inpatient Sample (NIS) database, we selected all adult patients admitted with a primary diagnosis of any GI malignancy from 2016 to 2020. We compared demographic characteristics as well as differences in in-hospital mortality, total hospital charges, and length of stay for patients who received a palliative care consultation during the admission and those who did not, with a goal of elucidating biases and informing future quality improvement efforts. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: There were 1,123,075 admissions with a primary diagnosis of a GI malignancy from 2016 to 2020, which represented 0.8% of total adult admissions.10.5% of admissions included a PC consultation. Rate of PC consultation varied based on the site of primary malignancy (see table). Patients for whom PC was consulted were older (69.3 vs. 66.2 years, p &lt; 0.01), less likely to be white (62.7% vs. 67.1%, p &lt; 0.01), and more likely to have Medicare (60.4 vs. 55.5, p &lt; 0.01). These patients were 12.8 times more likely to die during admission (mortality 24.2% vs. 1.9%, p &lt; 0.01), had longer lengths of stay (8.5 vs. 6.9 days, p &lt; 0.01) and lower total charges (84,400.2 vs. 96,637.6 USD, p &lt; 0.01). Conclusions: Early PC involvement in cancer care has been associated with improvement in quality of life and decreases in costs and readmissions. Rates of PC involvement in our cohort were overall low. Different rates of consultations for different races signal possible provider bias. The significantly higher mortality in patients who received a PC consult reflects the still current practice of involving PC only at the end of life. Quality improvement efforts should focus on eliminating biases and implementing strategies to maximize early palliative care utilization among patients with locally advanced or metastatic GI malignancies. [Table: see text]
Clinical and biological activity of FLX475, an oral CCR4 antagonist, in advanced cancer.
Authors: Dirk G. Brockstedt, Adam Grant, Juraj Adamik, Damian Trujillo, Rakesh Kumar Goyal, William Ho, Shoji Ikeda, Qingfeng Zhu, Robert A. Anders, Mohsen Sabouri, Paul D Kassner
Journal: Journal of Clinical Oncology (2023)

2625 Background: FLX475 is a potent and selective CCR4 antagonist, designed to block the recruitment of immunosuppressive regulatory T cells (T reg ) into tumors without affecting healthy tissues. Blocking migration of T reg into the tumor microenvironment (TME) has the potential to restore antitumor immunity and synergize with a variety of conventional and immunotherapy-based approaches to overcome immune resistance and broaden clinical efficacy. In a recent interim clinical update from the ongoing FLX475-02 Phase 1/2 trial, evidence of monotherapy and combination activity were reported. FLX475 monotherapy induced complete responses in two of the six evaluable subjects enrolled with EBV+ NK/T cell lymphoma. In checkpoint inhibitor naïve non-small-cell lung cancer (NSCLC), 4/13 subjects (31%) had confirmed partial responses (PRs) following treatment with the combination of FLX475 and pembrolizumab. In this analysis we present biomarker data from patients with broad range of tumor types treated with FLX475 monotherapy. We provide evidence to substantiate the mechanism of action and support the combination of FLX475 with pembrolizumab. Methods: Flow cytometry was used to measure relative proportions of T reg in the periphery. CD8 and FOXP3 positive cells in tumor biopsies were quantified by immunohistochemistry (IHC).Gene set enrichment analysis and immune deconvolution methods were used to interrogate RNAseq data derived from tumor biopsies. Results: FLX475 monotherapy results in a small but significant increase in proportion of circulating CD25+CD127-/low CD4+ T reg by day 8 of treatment. IHC analysis revealed a trend towards increased CD8:FOXP3 ratio in the TME of patient biopsies. Transcriptomic profiles from tumor biopsies of FLX475 monotherapy treated patients exhibited significant changes in immune pathways likely to benefit the antitumor response. Using global gene expression analyses we identified that FLX475 monotherapy altered the transcriptome of tumors to resemble those from patients with favorable clinical outcome to anti-PD(L)-1 treatment. Consistent with the proposed mechanism of action, immune deconvolution identified that FLX475-treated patients experienced a decrease in T reg cell populations. Conclusions: FLX475 monotherapy results in beneficial changes in the TME consistent with our proposed mechanism of action. FLX475 monotherapy is modifying the tumor microenvironment toward a phenotype associated with response to anti-PD-1/anti-PD-L1. Clinical trial information: NCT03674567 .
Anlotinib for patients with newly diagnosed glioblastoma with unmethylated MGMT promoter: An open-label, single-center, phase 2 clinical trial.
Authors: Kunyu Yang, Bian Wu, Zhanjie Zhang, Gang Peng, Jing Huang, Xiaohua Hong, Qian Ding, Liangliang Shi, Xuan Wang, Hongyang Zhao, Xiaobing Jiang
Journal: Journal of Clinical Oncology (2023)

e14039 Background: Glioblastoma (GBM) is the most common primary malignant brain tumor and one of the most deadly forms of cancer in humans. Given the temozolomide’s minimal benefit in O 6 -methylguanine-DNA Methyltransferase (MGMT) unmethylated GBM, new and effective therapies are urgently needed. In this study, we aimed to assess the safety and efficacy of anlotinib, a novel multitarget tyrosine kinase inhibitor for VEGFR, PDGFR, and c-Kit, in patients with MGMT unmethylated GBM. Methods: This was an open-label, single -center, single-arm, phase 2 trial. Eligible patients included those aged 18 to 70 years who had newly diagnosed histologically confirmed GBM with unmethylated MGMT promoter region. The cutoff value ≥ 10% was used to classify MGMT methylated vs. unmethylated cases. After initial surgical resection, patients with GBM received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and anlotinib (beginning on day 43 after surgery, at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle), followed by 6 cycles of maintenance therapy with anlotinib (at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle). Patients were re-evaluated every six weeks. The primary endpoint was progression-free survival (PFS), which is defined as the interval from the initiation of anlotinib treatment until the date of disease progression or death. The secondary endpoints were overall survival (OS) and safety. Standard Response Assessment in Neuro-Oncology (RANO) criteria were used to determine tumor response and progression. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. This trial was registered with chictr.org.cn, ChiCTR2000040116. Results: A total of 32 participants were enrolled from September 2020 to June 2022. All patients were with IDH wild-type and MGMT unmethylated status. The median age was 50 years (range, 27-65), and 19 (59.4%) were male. The median follow-up duration was 14.8 months (range, 5.5-23.7). The median PFS was 10.5 months (95%CI: 8.5-12.5), and the median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 13 (40.6%) patients of patients and grade 3 adverse events were observed in 4 (12.5%) patients. The most common toxicities were hypertension (13 [41%]), hand-foot syndrome (12 [38%]), hematuresis (9 [28%]) and liver dysfunction (5 [16%]). Grade 3 therapy-related adverse events included liver dysfunction (2 [6.3%]), hypertension (1 [3.1%]), hand-foot syndrome (1 [3.1%]). No grade 4-5 or unexpected adverse events were observed. Conclusions: This preliminary analysis suggested that anlotinib had promising efficacy and favorable tolerance as treatment of newly diagnosed GBM with unmethylated MGMT promoter. Clinical trial information: ChiCTR2000040116 .
Efficacy of STC-1010, a new allogenic cancer vaccine in colorectal cancer models.
Authors: Benoit You, Corinne Tortorelli, Yan Wang, Arnaud Peyronnier, Alban Bessede, Céline Gongora, Benoit Pinteur, Lionel Chalus, George Alzeeb, Paul Bravetti, François Ghiringhelli
Journal: Journal of Clinical Oncology (2023)

e14661 Background: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Recent tremendous progresses have installed immunotherapy as a treatment option and opened multiple ways to address therapeutic challenges for MSI or MSS CRC patients. Accordingly, Brenus-Pharma developed a therapeutic cancer vaccine, the STC-1010, basing on the technology by stimulating tumor cells (STC) with physical (irradiation and heat shock) and chemical (via standard-of-care (SoC) chemotherapy) stress, coupled with the haptenization for overexpressing tumor-related antigens. Methods: The mouse version of STC-1010 (mSTC-1010) vaccine prepared using two CRC mouse cell lines (CT26 and CMT93) and one pancreatic cancer mouse cell line (LTPA), previously showed encouraging results in pre-clinical studies on MSS CT26 ‘cold-tumor’ and anti-PD1 resistant MSI MC38 ‘hot-tumor’ murine models. mSTC-1010 associated with immunostimulant (cyclophosphamide and GM-CSF at low doses), combined or not with chemotherapy (FOLFOX or FOLFIRI) led to a significant decrease of tumor volume, a M1-oriented macrophage response (immunohistochemical, iNOS/CD163 &gt; 1), and an increase of T lymphocyte infiltration. Results: We confirmed these proof-of-concept efficacy with the human STC-1010 using three CRC human cell lines (HCT116, HT29 and Lovo). STC-1010 favored ex vivo an immune stimulation on human dendritic cells (DCs) which further primed CD8+ T cells to induce massive apoptosis of CRC cells (versus control). In HT29 in-ovo chicken embryo Chorio-Allantoid Membrane (CAM) assay, STC-1010 significatively increased IL-12, IL-2 and IFN-gamma expression (versus control) (p &lt; 0.02). Results from this immune reactive model showed significant increase of tumor necrosis (p = 0,0267), metastasis regression (-49%), and increase infiltration of CD4+, CD8+ compared to control group. Conclusions: The good tolerability of the STC-1010 vaccine in different models allows to plan a first-in-human phase I/II clinical trial with MSS and MSI-H metastatic CRC (mCRC) patients. A dose-escalation phase Ia (STC-1010 plus immunostimulant, associated to mFOLFOX6 w/o bevacizumab) will be performed with MSS mCRC patients to evaluate the safety and the recommended phase 2 trial dose (RP2D). A subsequent expansion phase IIa part will assess STC-1010 efficiency, associated with SoC in first-line setting for MSS patients, and in second-line setting after immunotherapy for MSI-H, dMMR or Lynch syndrome mCRC patients.
Clinical outcomes in phase 1 clinical trials (Ph1-CT) when treating patients (pts) with novel immunotherapy (IT) agents at early lines for advanced disease.
Authors: Juan José Soto, Sandra Llop-Serna, Agostina Stradella, Rafael Villanueva, Mariona Calvo, Maria Jove, Jose Carlos Ruffinelli, Carmen Cuadra Amor, Ramon Salazar, Miguel J. Gil Gil, Marta Gil-Martin, Marc Oliva, Juan Martin Liberal
Journal: Journal of Clinical Oncology (2023)

2586 Background: Cancer pts can be offered IT drugs within Ph1-CT before having exhausted standard of care (SoC) therapies. However, whether this strategy may improve pts’ outcomes remains unclear. We assess the benefits of receiving novel IT compounds within Ph1-CT at early lines for advanced disease. Methods: We retrospectively reviewed a correlative series of pts with advanced solid tumors treated with IT within Ph1-CT at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain, from January 2018 to July 2022. Primary aim was to assess clinical outcomes measured by median progression-free survival (mPFS) and median overall survival (mOS) according to number of prior lines (PL) for recurrent/metastatic disease, prior IT, availability of alternative SoC in our country, IT biomarker-selected population and grade 3-4 toxicity (G3-4 Tox) by multivariate analysis (MVA). Overall response rate (ORR) was evaluated by RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response + stable disease for ≥6 months (m). PFS/OS were calculated by Kaplan-Meier method. Log-rank test was used for comparisons. MVA was performed by Cox regression. Results: A total of 228 pts were assessed: IT monotherapy = 49 (21.5%), IT combinations = 179 (78.5%) (IT+IT = 111 [48.7%], IT+targeted therapy = 24 [10.5%], IT+others = 44 [19.3%]). Forty-nine (21.5%) pts were included according to IT biomarkers (PDL1, TIM3 expression, MSI-H, others). Median age was 62 y (24-83), 62.7% were men. All pts had ECOG ≤1. The 4 most frequent cancer types were HNSCC (19.7%), NSCLC (15.4%), glioblastoma (10.5%) and urothelial (10.1%). Number of PL: 0 = 33 (14.5%) pts, 1 = 92 (40.3%) pts, ≥2 = 103 (45.2%) pts. Sixty-three (27.6%) pts had received prior IT and 159 (69.7%) had alternative available SoC. Overall G3-4 Tox rate was 21.5% (20.6% in pts IT-treated). ORR and CBR were higher in pts IT-naïve than in pts IT-treated (21.2% vs 12.7% [p .18] and 35.7% vs 25.4% [p .26], respectively). With a median follow-up of 19m, overall mPFS and mOS were 3.5m (2.7-3.9) and 9.8m (8.5-11.5), respectively. In the MVA, lesser number of PL, SoC availability and biomarker selection positively impacted on mOS. After Ph1-CT treatment, 111 (48.7%) pts received further treatment: 19.3% within clinical trial, 29.4% with SoC. Conclusions: In our cohort of pts treated within IT Ph1-CT, those with less PL of treatment, with available alternative SoC and/or selected by biomarker achieved higher PFS and OS. These results suggest that treating pts with novel IT agents at early lines might positively impact on survival. [Table: see text]
Assessment of electronic health record (EHR) –based machine learning (ML) in predicting risk of brain metastasis among patients with early-stage non–small-cell lung cancer (eNSCLC).
Authors: Hossein Honarvar, Deep K Hathi, Ravi Bharat Parikh, Rahul K Das
Journal: Journal of Clinical Oncology (2023)

2036 Background: Among patients (pts) with eNSCLC, development ofbrain metastasis (BM) is a poor prognostic sign, but routine surveillance for BM is not recommended post-therapy. EHR-based ML algorithms may identify pts who would benefit from active brain MRI surveillance and/or treatment intensification in the early-stage setting. Methods: ConcertAI Patient360 database, consisting of structured and curated EHR records from pts receiving care in ~900 US oncology clinics, was used to identify pts diagnosed with stage IB-IIIA NSCLC without prior evidence of BM between Jan 2010 – December 2021. Presence of BM was identified from human curation of patient documents. Gradient boosting (GB), random forest (RF), and logistic regression (LR) algorithms with 3-fold cross-validation were trained and compared to predict risk of BM at two landmarks: 18 and 24 months (mos) from initial diagnosis (index). Pts who did not develop BM and either died or were lost to follow-up prior to landmark times were removed. Feature importance was defined using Shapley Additive Explanation (SHAP)-derived marginal odds ratios (OR). Due to low prevalence of BM, AUPRC was used as performance metric. Pts in the 1 st and 4 th quartiles of predicted probabilities from GB model were flagged as low-risk vs. high-risk. Results: Among 7473 pts in 18 mos model, median age was 68.4 years (IQR 13.2), 50.5% were female, and 10.9% were black. Demographics were similar for 6863 pts in 24 mos model. 6.4% and 8.3% developed BM at 18 and 24 mos. Ability of GB, RF, and LR models to predict BM was similar with validation AUPRC of 0.109 at 18 mos and 0.137 at 24 mos. In the GB model, BM prevalence in high-risk vs. low-risk group was 10.3% vs. 3.1% at 18 mos and 13.4% vs. 4.4% at 24 mos. In both landmark models, N0 stage and surgery within 90 days after index diagnosis were protective against BM, while presence of EGFR targetable mutations, adenocarcinoma (AD) histology, higher platelets (PLT), and history of pneumonia were risk factors. A glucose-by-histology interaction was found: For pts with normal blood glucose (GLU), risk of BM was independent of histology, for pts with high GLU, AD conferred greater risk of BM. Conclusions: An EHR-based ML model identified risk factors for developing BM among pts with eNSCLC and may identify pts who would benefit from active brain MRI surveillance and treatment intensification. [Table: see text]
A phase 0/2 trigger trial of niraparib in patients with newly diagnosed glioblastoma.
Authors: Shwetal Mehta, Nader Sanai, Tigran Margaryan, Jennifer Molloy, Hualin Zhang, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, Kelly Braun, William R. Kennedy, Michael A. Garcia, Igor J. Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan
Journal: Journal of Clinical Oncology (2023)

2069 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. Methods: Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. Results: All patients (n=35) enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 253.2 nM in 32 evaluable GBM patients. The suppression of PAR levels after ex vivo radiation was observed in 75% of the patients (18/24). Eleven out of 18 patients with unmethylated tumors enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], PFS6 was 64% (n=11) with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Conclusions: Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Clinical trial information: NCT05076513 .